A N-heterocyclic carbene derived highly regioselective ambident C-C-S and C-C-N 1,3-dipolar system

Article abstract of DOI:10.1039/b517700f

N-Heterocyclic carbene derived 2-phenylthiocarbamoyl benzimidazolium and imidazolinium inner salts are a unique ambident C-C-S and C-C-N 1,3-dipolar system able to undergo highly efficient and regioselective cycloaddition with dimethyl acetylenedicarboxyl

Full text of DOI:10.1039/b517700f

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A N-heterocyclic carbene derived highly regioselective ambident C–C–S
and C–C–N 1,3-dipolar system{
Mei-Fang Liu, Bo Wang and Ying Cheng*
Received (in Cambridge, UK) 14th December 2005, Accepted 19th January 2006
First published as an Advance Article on the web 1st February 2006
DOI: 10.1039/b517700f
first time that 1,3-dialkyl-2-phenylthiocarbamoyl-benzimidazolium
and -imidazolinium inner salts, readily formed from the interaction
of benzimidazole carbenes and imidazoline carbenes with phenyl
isothiocyanate, actually behave as the novel ambident C–C–S or
C–C–N (Fig. 1, C) 1,3-dipolar components. They undergo highly
efficient 1,3-dipolar cycloaddition reactions with dimethyl acet-
ylenedicarboxylate (DMAD) to furnish spiro[benzimidazoline-
2,39-thiophenes] or spiro[imidazolidine-2,39-thiophenes] as the
predominant products, while with ethyl propiolate, spiro[benzimi-
dazoline-2,39-pyrroles] or spiro[imidazolidine-2,39-pyrroles] are
obtained in good to excellent yields. Here, we report our
observations.
N-Heterocyclic carbene derived 2-phenylthiocarbamoyl benz-
imidazolium and imidazolinium inner salts are a unique
ambident C–C–S and C–C–N 1,3-dipolar system able to
undergo highly efficient and regioselective cycloaddition with
dimethyl acetylenedicarboxylate and ethyl propiolate to furnish,
respectively, spiro[imidazole-2,39-thiophene] and spiro[imida-
zole-2,39-pyrrole] derivatives in good to excellent yields.
Since Huisgen’s milestone work in the 1960s,1 1,3-dipolar
cycloaddition reactions have been developed into powerful
protocols for the construction of various five-membered ring
heterocycles.2 They have also found wide application in the
synthesis of natural products and organic compounds of biological
importance.2 Most of the 1,3-dipolar systems reported to date are
either of propyl–allenyl type (Fig. 1, A), including diazoalkanes,
nitrile ylides, nitrile imines, nitrile oxides and azides, or allyl type
(Fig. 1, B), such as azomethine ylides, azomethine imines and
nitrones. Both types contain a central heteroatom, such as nitrogen
or oxygen (Y = O or N), because their lone pair electrons can
participate in the stabilization of zwitterionic resonance structures.
Although carbon-centered 1,3-dipoles (Y = C) were proposed
decades ago,3–6 their chemistry has scarcely been explored. Only
2-arylthiocarbamoyl imidazolinium salts, for example, were
claimed as the C–C–N 1,3-dipolar component to undergo
cycloaddition with electron deficient alkenes or alkynes to give
spiro[4H-imidazole-2,39-pyrrole] derivatives (Scheme 1).3,4
In practice, benzimidazole carbenes or imidazoline carbenes
were generated in situ by deprotonation of the corresponding
benzimidazolium or imidazolinium salt using sodium hydride. The
carbenes formed reacted with phenyl isothiocyanate at room
temperature to form crystalline 2-phenylthiocarbamoyl benzimi-
dazolium inner salts 1 or imidazolinium inner salts 2 in the yields
of 63–89%. When treated with one equivalent of DMAD in
1,2-dichloroethane at ambient temperature, the zwitterionic
intermediates 1 were very rapidly transformed into spiro[benzimi-
dazoline-2,39-dihydrothiophenes] 3 in 90–95% yield. In addition to
the red-purple thiophene product 3, only a tiny amount of dark
green colored spiro[benzimidazoline-2,39-dihydropyrrole] 4 was
observed (Scheme 2). As demonstrated in Table 1, all of the
zwitterionic adducts 1 or 2, derived from both benzimidazole and
imidazoline carbenes, act as predominantly C–C–S rather than
C–C–N 1,3-dipolar systems to afford dihydrothiophene products 3
or 5 in excellent yields. It should be noted that these reactions are
in sharp contrast to those documented in the literature.3
As a part of our ongoing research project on the chemistry of
heteroatom-substituted carbenes,7 we investigated the three-
component reaction of N-heterocyclic carbenes with phenyl
isothiocyanate and electron deficient alkynes. We found for the
When zwitterions 1 and 2 were allowed to react with ethyl
propiolate under identical conditions to those for DMAD, the
reaction proceeded very slowly. Only at an elevated temperature
(60–80 uC) using either a large excess of ethyl propiolate or a
prolonged reaction period (5–28 h) did the reaction go to
completion (see supporting information{). Most surprisingly,
however, in all cases, the reaction led to the formation of
C–C–N 1,3-dipolar cycloaddition adducts spiro[benzimidazoline-2,
Fig. 1
Chemistry Department, Beijing Normal University, Beijing 100875,
China. E-mail: ycheng2@bnu.edu.cn; Fax: (+86) 10-58802075;
Tel: (+86) 10-58805558
{ Electronic supplementary information (ESI) available: Experimental
procedures and full characterization for all new compounds. See DOI:
10.1039/b517700f
Scheme 1
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Scheme 2
Scheme 3
Table 1 Cycloaddition reactions between salts 1 or 2 and DMAD
Starting
Yield
material R1 and R2 1 or 2 : DMAD Solvent Product (%)
Table 2 Cycloaddition reactions between salts 1 or 2 and ethyl
propiolate
1a
1b
1c
1d
1e
1f
Et
Et
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
b
DCEa
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
93
b
Starting
material R1 and R2
1 or 2 : ethyl
propiolate
Yield
(%)
—
90
4
Solvent Product
nBu
nBu
Bz
1a
1b
1c
1d
1e
1f
Et
Et
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
b
DCEa
DCE
DCE
DCE
DCE
DCE
DCE
THF
THF
7a
8a
7b
8b
7c
8c
7d
8d
7e
8e
7f
84
—
80
—
82
8
87
—
86
—
85
7
82
—
73
15
71
15
95
—
92
—
90
—
91
—
94
4
95
—
93
—
94
—
92
3
b
Bz
nBu
nBu
Bz
Et
nBu
iPr
Bz
nBu
Et
Et
nBu
iPr
Bz
4f
1g
2a
2b
2c
2d
2e
nBu
Bz
3g
4g
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
nBu
Et
Et
Et
Bz
8f
1g
2d
2e
nBu
Bz
7g
8g
9d
10d
9e
10e
nBu
nBu
tBu
tBu
Bz
Bz
Bz
MeOBz
MeOBz
Bz
MeOBz
MeOBz
a
DCE = 1,2-dichloroethane. A tiny amount of the minor product
93
2
was observed.
a
DCE = 1,2-dichloroethane. A tiny amount of the minor product
was observed.
determined unambiguously by single crystal X-ray diffraction
analysis (Fig. 2).{
39-dihydropyrroles] 7 or spiro[imidazolidine-2,39-dihydropyrroles]
9 as the major products (71–87%). Dihydrothiophene products 8
and 10 were isolated only as by-products in 7–15% yield (see
Scheme 3 and Table 2).
The high and ambident 1,3-dipolar cycloaddition reactivity of
2-phenylthiocarbamoyl-benzimidazolium and -imidazolinium
inner salts and, in particular, their clear cut cycloaddition reaction
pathways between C–C–S and C–C–N 1,3-dipolar systems when
treated with DMAD and ethyl propiolate, respectively, is
remarkable and intriguing. For example, the use of various
organic solvents, including THF, acetone, 1,2-dichloroethane and
acetonitrile, at different temperatures did not affect the reaction
pathway. As indicated in Table 1, the substituents on the nitrogen
atoms of the imidazoline ring also have negligible effect on the
outcome of the reaction. In order to shed light on the different
The structures of all products were fully characterized from their
spectroscopic data and by microanalysis. It is worth noting that
the dihydrothiophene products 3, 5, 8 and 10 gave their 13C-NMR
diagnostic CLN signal at 165–170 ppm while dihydropyrrole
compounds 4, 6, 7 and 9 showed their CLS carbon signal in a
downfield range between 200 and 210 ppm. To identify the isomers
beyond doubt, the structures of 3c, 4b, 5c and 7c were also
1216 | Chem. Commun., 2006, 1215–1217
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spiro[imidazole-2,39-pyrrole] derivatives as the predominant pro-
ducts in good to excellent yields. This work has probably revealed
a new type of ambident 1,3-dipolar compound whose regioselec-
tivity in reactions might be regulated by the reactivities of its
reaction partners. A systematic study on the application of
ambident 1,3-dipolar systems in cycloaddition reactions with other
dipolarophiles along with a mechanistic study are under way in
our laboratory.
This work was supported by the National Natural Science
Foundation of China for Distinguished Young Scholars (no.
20525207), the Program for New Century Excellent Talents in
University (no. NCET-04-0143) and the Key Project of the
Chinese Ministry of Education (no. 104014). We thank Ms. Ling
Wang for the computational calculations.
Notes and references
{ Crystal data for 3c: C34H29N3O4S, M = 575.66, T = 293 K, triclinic,
space group P-1, a = 11.114(3), b = 14.156(3), c = 19.352(5) s, a =
80.220(4), b = 85.469(4), c = 89.231(4)u, V = 2991.0(12) s3, Z = 4, rcalcd
=
Fig. 2 ORTEP drawings of the single-crystal structures of compounds
3c, 4b, 5c and 7c.§
1.278 g cm23, absorption coefficient 0.151 mm21, reflections collected/
unique 16183/10405 [Rint = 0.0362], final R indices [I > 2s(I)] R1 = 0.0547,
wR2 = 0.1239. 4b: C28H33N3O4S, M = 507.63, T = 294 K, monoclinic,
space group P2(1)/n, a = 10.175(18), b = 20.817(4), c = 13.993(3) s, a =
selectivity of zwitterionic species in the reaction with DMAD and
ethyl propiolate, the relative energies of two pairs of isomers, 3c
and 4c, and 7c and 8c, were calculated on the basis of their
B3LYP/6-31G* optimized structures. The calculation showed
that spiro[2H-benzimidazole-2,39-2H-thiophene] derivatives 3c
(9.639 kcal mol21) and 8c (10.798 kcal mol21) have much higher
relative energies than spiro[2H-benzimidazole-2,39-2H-pyrrole]
isomers 4c (0.000 kcal mol21) and 7c (0.000 kcal mol21). The
formation of pyrrole derivatives, i.e. the cycloaddition proceeding
through a C–C–N 1,3-dipolar component, is apparently thermo-
dynamically controlled. As such, the reaction requires heating, a
lengthy reaction time or an excess amount of the 1,3-dipolarophile.
The cycloaddition of the C–C–S 1,3-dipolar moiety of 1 or 2 onto
DMAD, on the other hand, proceeds through a kinetically favored
route to afford thiophene adducts rapidly and irreversibly because
DMAD is a stronger 1,3-dipolarophile. The unique ambident 1,3-
dipolar cycloaddition reactivity of zwitterions 1 and 2 lies in their
structure, in which the positive charge on the terminal carbon is
stabilized by its adjacent nitrogen atoms while the negative charge
is delocalized onto the sulfur and nitrogen of thiocarbamoyl group
(Fig. 1, C).
90.00, b = 108.821(3), c = 90.00u, V = 2805.4(9) s3, Z = 4, rcalcd
=
1.202 g cm23, absorption coefficient 0.152 mm21, reflections collected/
unique 15800/5760 [Rint = 0.0454], final R indices [I > 2s(I)] R1 = 0.0529,
wR2 = 0.1351. 5c: C24H33N3O4S, M = 459.60, T = 293 K, triclinic, space
group P-1, a = 10.097(2), b = 10.422(2), c = 13.951(3) s, a = 73.04, b =
69.52(3), c = 66.32u, V = 1239.9(4) s3, Z = 2, rcalcd = 1.231 g cm23
,
absorption coefficient 0.164 mm21, reflections collected/unique 5630/5630
[Rint = 0.000], final R indices [I > 2s(I)] R1 = 0.0654, wR2 = 0.1742. 7c:
C33H29N3O2S, M = 531.65, T = 294 K, triclinic, space group P-1, a =
9.7945(18), b = 10.295(2), c = 14.282(2) s, a = 70.912, b = 88.222(3), c =
89.992u, V = 1360.2(5) s3, Z = 2, rcalcd = 1.298 g cm23, absorption
coefficient 0.155 mm21, reflections collected/unique 7402/4731 [Rint
=
0.0263], final R indices [I > 2s(I)] R1 = 0.0468, wR2 = 0.1023. CCDC
286158 (3c), 286159 (4b), 286160 (5c) and 286161 (7c). For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b517700f
§ 50% probability was chosen for the ellipsoids. There are two independent
molecules of 3c in the asymmetric unit, only one of which is shown in
Fig. 2.
1 R. Huisgen, Proc. Chem. Soc., London, 1961, 357; R. Huisgen, Chem.
Weekbl., 1963, 59, 89.
2 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa, John Wiley & Sons,
New York, 1984; Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products, ed. A. Padwa and
W. H. Pearson, John Wiley & Sons, New York, 2002.
3 H. E. Winberg and D. D. Coffman, J. Am. Chem. Soc., 1965, 87, 2776.
4 M. Regitz, J. Hocker, W. Scho¨ssler, B. Weber and A. Liedhegener,
Liebigs Ann. Chem., 1971, 748, 1.
5 M. Regitz and J. Hocker, Synthesis, 1970, 301.
6 R. W. Hoffmann, B. Hagenbruch and D. M. Smith, Chem. Ber., 1977,
110, 23.
In summary, we have discovered for the first time that the
N-heterocyclic carbenes derived from 2-phenylthiocarbamoyl-
benzimidazolium and -imidazolinium inner salts are a unique type
of stable ambident C–C–S and C–C–N 1,3-dipolar system. They
are able to undergo highly efficient and regioselective 1,3-dipolar
cycloaddition reactions with DMAD and ethyl propiolate
to furnish, respectively, spiro[imidazole-2,39-thiophene] and
7 Y. Cheng, Q. Zhu, Q.-S. Li and O. Meth-Cohn, J. Org. Chem., 2005, 70,
4840; Y. Cheng and O. Meth-Cohn, Chem. Rev., 2004, 104, 2507;
Y. Cheng, H. Yang and O. Meth-Cohn, Chem. Commun., 2003, 90.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 1215–1217 | 1217